Founder genetic variants of <i>ABCC4</i> and <i>ABCC11</i> in the Japanese population are not associated with the development of subacute myelo‐optico‐neuropathy (SMON)

Matsumoto, Hideki; Sasai, Hideo; Kawamoto, Norio; Katsuyama, Masato; Minamiyama, Makoto; Kuru, Satoshi; Fukao, Toshiyuki; Ohnishi, Hiroyuki

doi:10.1002/mgg3.1845

Cited by 3 publications

(4 citation statements)

References 25 publications

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“…Comprehensive analyses, including analyses of all SNPs in NQO1, and identification of drug-sensitivity genes are required in future research. This study had limitations similar to those reported previously (Matsumoto et al, 2022). In particular, data for the total dose and duration of clioquinol administration in patients with SMON were lacking.…”

Section: Discussionmentioning

confidence: 64%

“…Both the ABCC4 rs3765534 and the ABCC11 rs17822931 polymorphisms are more common in Japanese people than in Europeans. However, in our previous study, we did not detect an association between the development of SMON and these polymorphisms in the Japanese population (Matsumoto et al., 2022 ).…”

Section: Introductionmentioning

confidence: 57%

“…This study was based on samples used in a previous report (Matsumoto et al., 2022 ). The participants were Japanese SMON patients who participated in the “SMON health examination by the SMON research group members” (health screening specifically for SMON patients provided through a national policy) from 2016 to 2020 (total number of patients screened: 297).…”

Section: Methodsmentioning

confidence: 99%

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Loss‐of‐function polymorphisms in NQO1 are not associated with the development of subacute myelo‐optico‐neuropathy

Matsumoto,

Sasai,

Kawamoto

et al. 2024

Molec Gen & Gen Med

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BackgroundSubacute myelo‐optico‐neuropathy (SMON) is a neurological disorder associated with the administration of clioquinol, particularly at very high doses. Although clioquinol has been used worldwide, there was an outbreak of SMON in the 1950s–1970s in which the majority of cases were in Japan, prompting speculation that the unique genetic background of the Japanese population may have contributed to the development of SMON. Recently, a possible association between loss‐of‐function polymorphisms in NQO1 and the development of SMON has been reported. In this study, we analyzed the relationship between NQO1 polymorphisms and SMON in Japan.MethodsWe analyzed 125 Japanese patients with SMON. NQO1 loss‐of‐function polymorphisms (rs1800566, rs10517, rs689452, and rs689456) were evaluated. The allele frequency distribution of each polymorphism was compared between the patients and the healthy Japanese individuals (Human Genomic Variation Database and Integrative Japanese Genome Variation Database), as well as our in‐house healthy controls.ResultsThe frequencies of the loss‐of‐function NQO1 alleles in patients with SMON and the normal control group did not differ significantly.ConclusionWe conclude that known NQO1 polymorphisms are not associated with the development of SMON.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 57%

Section: Methodsmentioning

confidence: 99%

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Loss‐of‐function polymorphisms in NQO1 are not associated with the development of subacute myelo‐optico‐neuropathy

Matsumoto,

Sasai,

Kawamoto

et al. 2024

Molec Gen & Gen Med

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“…It was therefore proposed that a combination of impaired transporter function and transport inhibition by CQ, could trigger SMON pathology, while it could also explain the restriction of SMON to Japan ( Perez et al, 2019 ). However, clinical data suggests that ABCC4 and ABCC11 are not associated with the development of SMON ( Matsumoto et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

NQO1 protects against clioquinol toxicity

Chhetri

Dilek²,

Davies³

et al. 2022

Front. Pharmacol.

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Clioquinol (CQ) was widely used as oral antibiotic before being taken off the market in many countries in 1970, after it was linked to subacute myelo-optic neuropathy (SMON) in Japan, leading to vision loss with many patients left wheelchair-bound. The common pathology of CQ-associated SMON was reproduced in animals but none of the proposed modes of toxicity explained the restriction of CQ-induced SMON to Japan. Given a re-emergence of CQ and related analogues as neuroprotectants, it is crucial to understand the underlying mechanism of CQ-induced toxicity to prevent any potential CQ-associated risks to future patients. A small molecule screen to find drugs that induce mitochondrial dysfunction in vitro identified CQ and the structurally related 8-hydroxyquinoline (8-OHQ). Their mitochondrial liability, pro-oxidative and cytotoxic activity was subsequently confirmed in some cell lines but surprisingly not in others. Subsequent studies in isogenic cell lines demonstrated that the antioxidant protein NQO1 is differentially expressed in the cell lines tested and potently protects against CQ toxicity. CQ-induced reduction of cellular ATP levels, increased lipid peroxidation and elevated cell death was also attenuated by antioxidants, implicating oxidative stress as the core mechanism of CQ-induced toxicity. These in-vitro findings were replicated in zebrafish. Visual acuity in zebrafish larvae that do not express NQO1, was reduced by CQ in a dose-dependent manner, while CQ did not affect visual function in the adult zebrafish that express NQO1. Similarly, pharmacological inhibition of NQO1 activity resulted in CQ-induced oxidative stress in the retina and severe acute systemic toxicity in the adult fish. Given the much higher prevalence of the inactivating C609T NQO1 polymorphism in the Japanese population compared to the European population, the results of this study could for the first time indicate how the geographic restriction of SMON cases to Japan could be explained. Importantly, if CQ or its derivatives are to be used safely for the treatment of neurodegenerative diseases, it seems imperative that NQO1 levels and activity of prospective patients should be ascertained.

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Founder genetic variants of ABCC4 and ABCC11 in the Japanese population are not associated with the development of subacute myelo‐optico‐neuropathy (SMON)

Matsumoto

Sasai

Kawamoto

et al. 2021

Molec Gen & Gen Med

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Founder genetic variants of ABCC4 and ABCC11 in the Japanese population are not associated with the development of subacute myelo‐optico‐neuropathy (SMON)

Cited by 3 publications

References 25 publications

Loss‐of‐function polymorphisms in NQO1 are not associated with the development of subacute myelo‐optico‐neuropathy

Loss‐of‐function polymorphisms in NQO1 are not associated with the development of subacute myelo‐optico‐neuropathy

NQO1 protects against clioquinol toxicity

Founder genetic variants of ABCC4 and ABCC11 in the Japanese population are not associated with the development of subacute myelo‐optico‐neuropathy (SMON)

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